自由基介导的α-叔胺合成研究进展

doi:10.6023/cjoc202406040

摘要/Abstract

α-叔胺是一类在氮原子α位具有叔碳中心的胺类化合物. 由于叔碳中心的存在, α-叔胺在生物体内的脂溶性与代谢稳定性有所改变, 使其在药物研发领域具有重要的应用价值. 传统的α-叔胺合成方法包括: 酮亚胺的亲核加成、羰基化合物的亲电胺化、三级烯丙基亲电试剂的烯丙基胺化及重排反应等. 得益于自由基具有高活性、反应条件温和及良好的官能团兼容性, 自由基反应在合成α-叔胺方面表现出独特优势. 近年来, 发展出了烯烃的自由基胺化/氢胺烷基化、自由基碳氮交叉偶联、亚胺的自由基加成及烷烃的碳氢键活化等方法. 综述了近十年来自由基介导的分子间α-叔胺的合成方法, 并详细讨论了每种方法的特点.

关键词: α-叔胺, 自由基, 亚胺

α-Tertiary amines are a class of amine compounds with a tertiary carbon center at the α-position of the nitrogen atom. The presence of the tertiary carbon center significantly alters the lipid solubility and metabolic stability of α-tertiary amines in biological systems, making them valuable in pharmaceutical development. Traditional methods for the synthesis of α-tertiary amines include nucleophilic addition of ketimines, electrophilic amination of carbonyl compounds, allylic amination of tertiary allyl electrophiles, and rearrangement reactions. Due to the high reactivity, mild reaction conditions, and good functional group tolerance of the radical, radical reactions exhibit unique advantages in the synthesis of α-tertiary amines. Given the importance of α-tertiary amines and the advantages of radical reactions, various methods have been developed, including radical amination/hydroamination of alkenes, radical C—N cross-coupling, radical addition of imines, and C—H bond activation of alkanes. The radical-mediated intermolecular synthesis of α-tertiary amines over the past decade is summarized and the characteristics of each method is discussed in detail.

Key words: α-tertiary amine, radical, imine

引用此文

方家恒, 田润妍, 陈继君, 刘心元. 自由基介导的α-叔胺合成研究进展[J]. 有机化学, 2025, 45(1): 22-41.

Jiaheng Fang, Runyan Tian, Jijun Chen, Xinyuan Liu. Research Progress in the Synthesis of α-Tertiary Amines via Radical Strategies[J]. Chinese Journal of Organic Chemistry, 2025, 45(1): 22-41.

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图/表 36

图1. α-叔胺结构和自由基介导的α-叔胺合成方法汇总

Figure 1. Structures of α-tertiary amines and radical involved α-tertiary amines synthesis

图式1. 1,1-二取代烯烃的碳叠氮化反应

Scheme 1. Carboazidation of 1,1-disubstituted alkenes

图式2. 光催化1,3-共轭二烯的胺叠氮化反应

Scheme 2. Photoredox catalyzed amidoazidation of 1,3-dienes

图式3. 铁催化1,1-二取代烯烃的不对称碳叠氮化反应

Scheme 3. Iron-catalyzed asymmetric carboazidation of 1,1-di- substituted alkenes

图式4. 铁催化烷烃与1,1-二取代烯烃的不对称碳叠氮化反应

Scheme 4. Iron-catalyzed asymmetric carboazidation of 1,1-di- substituted alkenes with alkane

图式5. 铜催化1,1-二取代烯烃的不对称碳叠氮化反应

Scheme 5. Copper-catalyzed asymmetric carboazidation of 1,1- disubstituted alkenes

图式6. 铜催化烯烃与芳胺的三组分碳胺化反应

Scheme 6. Copper-catalyzed three-component carboamination of alkenes with arylamines

图式7. 铁催化的烯烃与芳硝基化物的氢胺化反应

Scheme 7. Iron-catalyzed olefin hydroamination with nitro- arenes

图式8. 光催化烯烃的三组分氢胺烷基化反应

Scheme 8. Photoredox catalyzed three-component hydroaminoalkylation of alkenes

图式9. 光催化保护的烷基胺与烯烃的氢胺烷基化反应

Scheme 9. Photoredox catalyzed olefin hydroaminoalkylation with protected alkyl amines

图式10. 光催化未保护的烷基胺与烯烃的氢胺烷基化反应

Scheme 10. Photoredox catalyzed olefin hydroaminoalkylation with unprotected alkyl amines

图式11. 电催化烯烃的三组分氢胺烷基化反应

Scheme 11. Electro-catalyzed three-component hydroaminoalkylation of alkenes

图式12. 铜催化芳基羟胺与α-溴代羰基化合物的交叉偶联反应

Scheme 12. Copper-catalyzed cross coupling of hydroxylamines with α-bromocarbonyls

图式13. 光-铜双催化三级氯代物与咔唑/吲哚的自由基不对称碳氮键交叉偶联反应

Scheme 13. Photoredox-copper dual catalyzed radical asymmetric C—N bond cross coupling of tertiary chloride with indole/carbazole

图式14. 钯催化的自由基碳氮交叉偶联反应

Scheme 14. Palladium-catalyzed radical C—N cross coupling

图式15. 光-铜双催化三级卤代物与芳胺的自由基不对称碳氮交叉偶联反应

Scheme 15. Photoredox-copper dual catalyzed radical asymmetric C—N bond cross coupling of tertiary halides with arylamines

图式16. 铜催化亚磺酰亚胺/芳胺的自由基不对称碳氮键交叉偶联反应

Scheme 16. Copper-catalyzed radical asymmetric C—N cross coupling with sulfoximines/arylamines

图式17. 铜催化的不对称霍夫曼N-烷基化反应

Scheme 17. Copper-catalyzed asymmetric Hoffman N-alkylation

图式18. 铜催化的氮杂芳胺/芳胺的自由基交叉偶联反应

Scheme 18. Copper-catalyzed radical cross coupling of hetero/aromatic amines

图式19. 光催化的酮亚胺与环己酮的β-Mannich反应

Scheme 19. Photoredox catalyzed β-Mannich reaction of ketimines with cyclohexanone

图式20. 光催化的三级溴代物与PhI=NNs/PhI=NT的自由基-自由基交叉偶联反应

Scheme 20. Photoredox-catalyzed radical-radical cross coupling of tertiary bromines with PhI=NNs/PhI=NT

图式21. 光催化DHP衍生物与酮亚胺的自由基-自由基交叉偶联反应

Scheme 21. Photoredox-catalyzed radical-radical cross coupling of DHPs with imines

图式22. 光催化的氨气与酮的自由基偶联反应

Scheme 22. Photoredox-catalyzed radical cross coupling of ammonia with ketone

图式23. 光催化的肟/亚胺与4-氰基吡啶的自由基-自由基交叉偶联反应

Scheme 23. Photoredox-catalyzed radical-radical cross coupling of oximes/imines with 4-cyanopyridine

图式24. 光催化的NHP酯与4-氰基吡啶的自由基-自由基交叉偶联反应

Scheme 24. Photoredox-catalyzed radical-radical cross coupling of NHP ester with 4-cyanopyridine

图式25. 光催化的烷烃与亚胺的自由基-自由基交叉偶联反应

Scheme 25. Photoredox-catalyzed radical-radical cross coupling of alkanes with imines

图式26. 烷基碘代物与三甲基锡基保护的亚胺的自由基加成反应

Scheme 26. Radical addition of trimethyltin protected imines with alkyl iodides

图式27. 光-铜双催化三氟硼酸钾盐与亚胺的自由基加成反应

Scheme 27. Photoredox-copper dual catalyzed radical addition of imines with alkyl trifluoroborate

图式28. 光-铜双催化烷烃与亚胺的自由基加成反应

Scheme 28. Photoredox-copper dual catalyzed radical addition of imines with alkanes

图式29. 光催化烷基胺/酮/烷基碘代物的三组分反应

Scheme 29. Photoredox-catalyzed three component reaction of alkyl amines, ketone and iodides

图式30. 锌-路易斯酸调控的胺/酮/烷基碘代物的三组分反应

Scheme 30. Zinc-Lewis acid catalyzed three component reaction of alkyl amines, ketone and iodides

图式31. 光-手性磷酸双催化DHPs与亚胺的自由基加成反应

Scheme 31. Photoredox-chiral phosphoric acid dual catalyzed radical addition of imines with DHPs

图式32. 钴催化的不对称aza-Barbier反应

Scheme 32. Cobalt-catalyzed asymmetric aza-Barbier reaction

图式33. 铁催化脂肪族烷烃的碳氢键叠氮化反应

Scheme 33. Iron-catalyzed C—H bond azidation of tertiary unactivated alkanes

图式34. 光电/锰催化非活化烷烃的碳氢键叠氮化反应

Scheme 34. Electrophotocatalytic/manganese-catalyzed C(sp3)—H bonds azidation of unactivated alkanes

图式35. 光-铈双催化链状烷烃的碳氢键胺化反应

Scheme 35. Photoredox-cerium dual catalyzed C—H bond amination of chain alkanes

参考文献 82

[1]	Hager, A.; Vrielink, N.; Hager, D.; Lefranc, J.; Trauner, D. Nat. Prod. Rep. 2016, 33, 491.
[2]	Wanka, L.; Iqbal, K.; Schreiner, P. R. Chem. Rev. 2013, 113, 3516.
[3]	Ramos-Gonzalez, N.; Paul, B.; Majumdar, S. Pharmacol. Res. 2023, 197, 106961.
[4]	Xu, Y.; Wang, J.; Deng, G.-J.; Shao, W. Chem. Commun. 2023, 59, 4099.
[5]	Kiyokawa, K.; Watanabe, T.; Fra, L.; Kojima, T.; Minakata, S. J. Org. Chem. 2017, 82, 11711.
[6]	Nakagawa, A.; Iwai, Y.; Hashimoto, H.; Miyazaki, N.; Oiwa, R.; Takahashi, Y.; Hirano, A.; Shibukawa, N.; Kojima, Y.; Omura, S. J. Antibiot. 1981, 34, 1408.
[7]	Kimura, T.; Suga, T.; Kameoka, M.; Ueno, M.; Inahashi, Y.; Matsuo, H.; Iwatsuki, M.; Shigemura, K.; Shiomi, K.; Takahashi, Y.; Omura, S.; Nakashima, T. J. Antibiot. 2019, 72, 169.
[8]	Morgenthaler, M.; Schweizer, E.; Hoffmann-Röder, A.; Benini, F.; Martin, R. E.; Jaeschke, G.; Wagner, B.; Fischer, H.; Bendels, S.; Zimmerli, D.; Schneider, J.; Diederich, F.; Kansy, M.; Müeller, K. ChemMedChem 2007, 2, 1100.
[9]	Shibasaki, M.; Kanai, M. Chem. Rev. 2008, 108, 2853.
[10]	Enders, D.; Gottfried, K.; Raabe, G. Adv. Synth. Catal. 2010, 352, 3147.
[11]	Bloch, R. Chem. Rev. 1998, 98, 1407.
[12]	Yamada, K.-I.; Tomioka, K. Chem. Rev. 2008, 108, 2874.
[13]	Kobayashi, S.; Mori, Y.; Fossey, J. S.; Salter, M. M. Chem. Rev. 2011, 111, 2626.
[14]	Curto, J. M.; Dickstein, J. S.; Berritt, S.; Kozlowski, M. C. Org. Lett. 2014, 16, 1948.
[15]	Wieland, L. C.; Vieira, E. M.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2008, 131, 570.
[16]	Trost, B. M.; Tracy, J. S.; Lin, E. Y. ACS Catal. 2019, 9, 11082.
[17]	Ohmatsu, K.; Ando, Y.; Nakashima, T.; Ooi, T. Chem 2016, 1, 802.
[18]	Guo, W.; Cai, A.; Xie, J.; Kleij, A. W. Angew. Chem., Int. Ed. 2017, 56, 11797.
[19]	Cai, A.; Guo, W.; Martínez-Rodríguez, L.; Kleij, A. W. J. Am. Chem. Soc. 2016, 138, 14194.
[20]	Arnold, J. S.; Nguyen, H. M. J. Am. Chem. Soc. 2012, 134, 8380.
[21]	Clayden, J.; Donnard, M.; Lefranc, J.; Tetlow, D. J. Chem. Commun. 2011, 47, 4624.
[22]	Iosub, V.; Haberl, A. R.; Leung, J.; Tang, M.; Vembaiyan, K.; Parvez, M.; Back, T. G. J. Org. Chem. 2010, 75, 1612.
[23]	Arnold, J. S.; Cizio, G. T.; Nguyen, H. M. Org. Lett. 2011, 13, 5576.
[24]	Romero, K. J.; Galliher, M. S.; Pratt, D. A.; Stephenson, C. R. J. Chem. Soc. Rev. 2018, 47, 7851.
[25]	Yan, M.; Lo, J. C.; Edwards, J. T.; Baran, P. S. J. Am. Chem. Soc. 2016, 138, 12692.
[26]	Gu, Q.-S.; Li, Z.-L.; Liu, X.-Y. Acc. Chem. Res. 2020, 53, 170.
[27]	Sibi, M. P.; Manyem, S.; Zimmerman, J. Chem. Rev. 2003, 103, 3263.
[28]	Bunescu, A.; Ha, T. M.; Wang, Q.; Zhu, J. Angew. Chem., Int. Ed. 2017, 56, 10555.
[29]	Bao, X.; Yokoe, T.; Ha, T. M.; Wang, Q.; Zhu, J. Nat. Commun. 2018, 9, 3725.
[30]	Forster, D.; Guo, W.; Wang, Q.; Zhu, J. ACS Catal. 2021, 11, 10871.
[31]	Carlson, A. S.; Topczewski, J. J. Org. Biomol. Chem. 2019, 17, 4406.
[32]	Lv, D.; Sun, Q.; Zhou, H.; Ge, L.; Qu, Y.; Li, T.; Ma, X.; Li, Y.; Bao, H. Angew. Chem., Int. Ed. 2021, 60, 12455.
[33]	Liu, W.; Pu, M.; He, J.; Zhang, T.; Dong, S.; Liu, X.; Wu, Y.-D.; Feng, X. J. Am. Chem. Soc. 2021, 143, 11856.
[34]	Ge, L.; Wang, H.; Liu, Y.; Feng, X. J. Am. Chem. Soc. 2024, 146, 13347.
[35]	Wu, L.; Zhang, Z.; Wu, D.; Wang, F.; Chen, P.; Lin, Z.; Liu, G. Angew. Chem., Int. Ed. 2021, 60, 6997.
[36]	Suh, S.-E.; Chen, S.-J.; Mandal, M.; Guzei, I. A.; Cramer, C. J.; Stahl, S. S. J. Am. Chem. Soc. 2020, 11388.
[37]	Gockel, S. N.; Buchanan, T. L.; Hull, K. L. J. Am. Chem. Soc. 2018, 140, 58.
[38]	Nicely, A. M.; Popov, A. G.; Wendlandt, H. C.; Trammel, G. L.; Kohler, D. G.; Hull, K. L. Org. Lett. 2023, 25, 5302.
[39]	Gui, J.; Pan, C.-M.; Jin, Y.; Qin, T.; Lo, J. C.; Lee, B. J.; Spergel, S. H.; Mertzman, M. E.; Pitts, W. J.; La Cruz, T. E.; Schmidt, M. A.; Darvatkar, N.; Natarajan, S. R.; Baran, P. S. Science 2015, 348, 886.
[40]	Zhu, K.; Shaver, M. P.; Thomas, S. P. Chem. Sci. 2016, 7, 3031.
[41]	Trowbridge, A.; Reich, D.; Gaunt, M. J. Nature 2018, 561, 522.
[42]	Henry Blackwell, J.; Harris, G. R.; Smith, M. A.; Gaunt, M. J. J. Am. Chem. Soc. 2021, 143, 15946.
[43]	Harris, G. R.; Trowbridge, A. D.; Gaunt, M. J. Org. Lett. 2023, 25, 861.
[44]	Ashley, M. A.; Yamauchi, C.; Chu, J. C. K.; Otsuka, S.; Yorimitsu, H.; Rovis, T. Angew. Chem., Int. Ed. 2019, 58, 4002.
[45]	Ye, J.; Kalvet, I.; Schoenebeck, F.; Rovis, T. Nat. Chem. 2018, 10, 1037.
[46]	Ryder, A. S. H.; Cunningham, W. B.; Ballantyne, G.; Mules, T.; Kinsella, A. G.; Turner-Dore, J.; Alder, C. M.; Edwards, L. J.; McKay, B. S. J.; Grayson, M. N.; Cresswell, A. J. Angew. Chem., Int. Ed. 2020, 59, 14986.
[47]	Askey, H. E.; Grayson, J. D.; Tibbetts, J. D.; Turner-Dore, J. C.; Holmes, J. M.; Kociok-Kohn, G.; Wrigley, G. L.; Cresswell, A. J. J. Am. Chem. Soc. 2021, 143, 15936.
[48]	Liu, W.-Q.; Lee, B. C.; Song, N.; He, Z.; Shen, Z.-A.; Lu, Y.; Koh, M. J. Angew. Chem., Int. Ed. 2024, 63, e202402140.
[49]	Fisher, D. J.; Burnett, G. L.; Velasco, R.; Read de Alaniz, J. J. Am. Chem. Soc. 2015, 137, 11614.
[50]	Janey, J. M. Angew. Chem., Int. Ed. 2005, 44, 4292.
[51]	Kainz, Q. M.; Matier, C. D.; Bartoszewicz, A.; Zultanski, S. L.; Peters, J. C.; Fu, G. C. Science 2016, 351, 681.
[52]	Peacock, D. M.; Roos, C. B.; Hartwig, J. F. ACS Cent. Sci. 2016, 2, 647.
[53]	Cho, H.; Suematsu, H.; Oyala, P. H.; Peters, J. C.; Fu, G. C. J. Am. Chem. Soc. 2022, 144, 4550.
[54]	Zhang, Y.-F.; Wang, J.-H.; Yang, N.-Y.; Chen, Z.; Wang, L.-L.; Gu, Q.-S.; Li, Z.-L.; Liu, X.-Y. Angew. Chem., Int. Ed. 2023, 62, e202302983.
[55]	Chen, J.-J.; Zhang, J.-Y.; Fang, J.-H.; Du, X.-Y.; Xia, H.-D.; Cheng, B.; Li, N.; Yu, Z.-L.; Bian, J.-Q.; Wang, F.-L.; Zheng, J.-J.; Liu, W.-L.; Gu, Q.-S.; Li, Z.-L.; Liu, X.-Y. J. Am. Chem. Soc. 2023, 145, 14686.
[56]	Zheng, J.-J.; Liu, W.-L.; Gu, Q.-S.; Li, Z.-L.; Chen, J.-J.; Liu, X.-Y. Precis. Chem. 2023, 1, 576.
[57]	Chen, J.-J.; Fang, J.-H.; Du, X.-Y.; Zhang, J.-Y.; Bian, J.-Q.; Wang, F.-L.; Luan, C.; Liu, W.-L.; Liu, J.-R.; Dong, X.-Y.; Li, Z.-L.; Gu, Q.-S.; Dong, Z.; Liu, X.-Y. Nature 2023, 618, 294.
[58]	Du, X.-Y.; Fang, J.-H.; Chen, J.-J.; Shen, B.; Liu, W.-L.; Zhang, J.-Y.; Ye, X.-M.; Yang, N.-Y.; Gu, Q.-S.; Li, Z.-L.; Yu, P.; Liu, X.-Y. J. Am. Chem. Soc. 2024, 146, 9444.
[59]	Gong, Y.; Zhu, Z.; Qian, Q.; Tong, W.; Gong, H. Org. Lett. 2021, 23, 1005.
[60]	Duan, G.; Qian, Q.; Chen, Y. Tetrahedron Lett. 2023, 129, 154730.
[61]	Jeffrey, J. L.; Petronijević, F. R.; MacMillan, D. W. C. J. Am. Chem. Soc. 2015, 137, 8404.
[62]	Brueckner, A. C.; Hancock, E. N.; Anders, E. J.; Tierney, M. M.; Morgan, H. R.; Scott, K. A.; Lamar, A. A. Org. Biomol. Chem. 2016, 14, 4387.
[63]	Zhang, H.-H.; Yu, S. J. Org. Chem. 2017, 82, 9995.
[64]	Rong, J. W.; Seeberger, P. H.; Gilmore, K. Org. Lett. 2018, 20, 4081.
[65]	Nicastri, M. C.; Lehnherr, D.; Lam, Y.-H.; DiRocco, D. A.; Rovis, T. J. Am. Chem. Soc. 2020, 142, 987.
[66]	Li, S.; Du, H.-W.; Davies, P. W.; Shu, W. CCS Chem. 2024, 6, 1060.
[67]	Tomono, R.; Kawasaki, T.; Ishida, N.; Murakami, M. Chem. Lett. 2021, 50, 1972.
[68]	Zhao, H.; Hu, Y.; Zheng, S.; Yuan, W. Org. Lett. 2023, 25, 6699.
[69]	Dickstein, J. S.; Kozlowski, M. C. Chem. Soc. Rev. 2008, 37, 1166.
[70]	Lamas, M.-C.; Vaillard, S. E.; Wibbeling, B.; Studer, A. Org. Lett. 2010, 12, 2072.
[71]	Li, Y.; Zhou, K.; Wen, Z.; Cao, S.; Shen, X.; Lei, M.; Gong, L. J. Am. Chem. Soc. 2018, 140, 15850.
[72]	Li, Y.; Lei, M.; Gong, L. Nat. Catal. 2019, 2, 1016.
[73]	Blackwell, J. H.; Kumar, R.; Gaunt, M. J. J. Am. Chem. Soc. 2021, 143, 1598.
[74]	Phelps, J. M.; Kumar, R.; Robinson, J. D.; Chu, J. C. K.; Flodén, N. J.; Beaton, S.; Gaunt, M. J. J. Am. Chem. Soc. 2024, 146, 9045.
[75]	Song, X.; Zhang, Y.; Li, Y.; Zhao, X.; Yin, Y.; Ban, X.; Jiang, Z. ACS Catal. 2023, 13, 6396.
[76]	Wu, X.; Xia, H.; Gao, C.; Luan, B.; Wu, L.; Zhang, C.; Yang, D.; Hou, L.; Liu, N.; Xia, T.; Li, H.; Qu, J.; Chen, Y. Nat. Chem. 2023, 16, 398.
[77]	Xia, T.; Wu, Y.; Hu, J.; Wu, X.; Qu, J.; Chen, Y. Angew. Chem., Int. Ed. 2024, 63, e202316012.
[78]	Xia, T.; Wu, W.; Wu, X.; Qu, J.; Chen, Y. Angew. Chem., Int. Ed. 2024, 63, e202318991.
[79]	Sharma, A.; Hartwig, J. F. Nature 2015, 517, 600.
[80]	Niu, L.; Jiang, C.; Liang, Y.; Liu, D.; Bu, F.; Shi, R.; Chen, H.; Chowdhury, A. D.; Lei, A. J. Am. Chem. Soc. 2020, 142, 17693.
[81]	Hu, A.; Guo, J.-J.; Pan, H.; Tang, H.; Gao, Z.; Zuo, Z. J. Am. Chem. Soc. 2018, 140, 1612.
[82]	An, Q.; Wang, Z.; Chen, Y.; Wang, X.; Zhang, K.; Pan, H.; Liu, W.; Zuo, Z. J. Am. Chem. Soc. 2020, 142, 6216.